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NAT2 (N-acetyltransferase 2 (arylamine N-acetyltransferase))

Written2009-01Jhon D Ruiz, José AG Agúndez, Carmen Martínez, Elena García-Martín
Department of Pharmacology, Medical School, University of Extremadura, Badajoz, Spain (JDR, JA, CM); Department of Biochemistry & Molecular biology & Genetics, School of Biological Sciences, Badajoz, Spain (EGM)

(Note : for Links provided by Atlas : click)

Identity

Alias_namesAAC2
N-acetyltransferase 2 (arylamine N-acetyltransferase)
Other aliasPNAT
HGNC (Hugo) NAT2
LocusID (NCBI) 10
Atlas_Id 41498
Location 8p22  [Link to chromosome band 8p22]
Location_base_pair Starts at 18391245 and ends at 18401213 bp from pter ( according to hg19-Feb_2009)  [Mapping NAT2.png]
 
  Picture from Genetics Home Reference; January 2009.
Note In humans NAT2 is located in the NAT cluster that comprises 230 kb and includes two functional genes, NAT1 and NAT2. In other species the number of NAT genes range from 0, for instance in dogs, to 4 for instance in chicken.

DNA/RNA

 
Transcription The human NAT2 gene has two exons but the coding region, spanning 870 bp is located in exon 2. Functionally active NAT2 enzyme can be obtained after transient heterologous transfection of the open reading frame only, indicating that exon 1 is not necessary to obtain functional enzyme.
Pseudogene In humans the NAT locus has a pseudogene designated as NATP.

Protein

Note NAT enzymes have been identified in several vertebrate and microorganism species. NAT2 proteins differ among species. However, common features include an 83 amino acid N-terminal domain containing five alpha-helices and a short beta-strand; a second domain consisting of nine beta-strands and two short helices; and a third alpha/beta lid domain with four beta-strands and an alpha-helix.
Expression NAT2 has a restricted expression profile with the highest levels of protein and mRNA being detected in the liver, small intestine and colon. The transcription start site for human NAT2 has been recently localised between 30 and 101 bp upstream of the non-coding exon, with the most frequent TSS located at position -64 relative to exon 1. The region containing the NAT2 transcription start site shares an 85% sequence homology to the region of human NAT1 containing the major transcription start site for NAT1. The functional elements of the NAT2 promoter sequence have not been characterised to date. In addtion the promoter sequence appears to be highly polymorphic.
Localisation Arylamine N-acetyltransferase 2 is a cytosolic enzyme.
Function NAT2 is a phase II enzyme that participates in the metabolism of numerous primary arylamines and hydrazine drugs and carcinogens. In addition to their N-acetylation catalytic activity, NAT enzymes have also O-acetylation activity towards N-hydroxyarylamines.
Homology NAT1 and NAT2 share 87% nucleotide homology in the coding region, whereas NAT1 and NAT2 proteins share 81% amino-acid sequence identity.

Mutations

Note Seven major single nucleotide polymorphisms that occur isolated or combined have been described in the NAT2 gene. These affect the positions 191, 282, 341, 481, 590, 803 and 857. In addition, rare SNPs affecting the positions 111, 190, 364, 411, 434, 499, 795, 845 and 859 have been described although their frequencies are unknown. For details on NAT2 SNPs and haplotypes, see http://louisville.edu/medschool/pharmacology/Human.NAT2.pdf. Critical gene variants leading to slow acetylation capacity contains mutations at positions 191, 341, 590 or 857. Since some genotypes can be due to the presence of different combinations of haplotypes leading to ambiguous phenotype prediction, haplotype reconstruction is often necessary to clarify ambiguous genotype data.
 

Implicated in

Note
Note Determination of the NAT2 genotype or phenotype has been proposed to predict adverse reactions in patients with tuberculosis receiving isoniazid, prior to the concomitant administration of drug combinations such as procainamide-phenytoin or doxiciline-rifampin. In addition, several human diseases have been related to NAT2 polymorphism. There are described below.
  
  
Entity Brain cancer
Prognosis Preliminary findings argue for association of a trend towards higher risk in individuals classified as NAT2 homozygous rapid acetylators in patients with astrocytoma or meningioma.
  
  
Entity Lung cancer
Prognosis Several studies based on an initial hypothesis that slow acetylation may increase the risk of developing lung cancer have been conducted. This hypothesis has been reinforced by studies indicating that slow acetylation, especially if it is associated to defect genotypes for other phase II enzymes, may confer increased susceptibility to the formation of adducts. Several studies have concluded that the NAT2 slow acetylation genotype causes a marginally increased risk of developing lung cancer. In spite of these findings, present evidence suggests that the NAT2 polymorphism alone does not constitute a relevant risk factor for lung cancer. However this polymorphism may reinforce the effect of other genetic and/or environmental factors.
  
  
Entity Liver cancer
Prognosis A role for xenobiotic-metabolising enzymes in liver carcinogenesis is to be expected among patients with environmentally-related liver cancer since, besides viral hepatitis, liver cancer may be related to environmental substances. The findings obtained in patients with primary liver cancer not related to viral hepatitis are consistent and indicate a minor, but relevant, association of the slow NAT2 acetylation status and predisposition to liver cancer.
  
  
Entity Colorectal cancer
Prognosis The hypothesis that acetylator status may predispose to a determined cancer risk is based on a differential effect of N-acetylation as a potential detoxification step and O-acetylation as a potential carcinogen-activation step. In the case of colorectal cancer it was hypothesized that O-acetylation is more relevant that N-acetylation, and therefore the rapid acetylation genotype is the putative risk status associated with colorectal cancer. Sufficient evidence is available to rule out a relevant association of NAT genotypes alone with colorectal cancer risk. However, the putative interaction of meat consumption and the NAT2 genotype deserves particular attention.
  
  
Entity Bladder cancer
Prognosis Despite the large number of studies and meta-analyses performed in several human populations, current evidence is not sufficient to confirm unambiguously an association of NAT2 polymorphism to overall bladder cancer risk. A general association of the slow acetylation status with bladder cancer risk has not been fully confirmed, although meta-analyses have obtained positive findings for a modest association of the slow NAT2 acetylation genotype with bladder cancer risk, with odds ratio values between 1.3 and 1.5. Furthermore, the biological basis for the putative association is uncertain. In diverse independent studies, mutagenicity in urine was tested in individuals exposed to urban pollution, smoking, red meat intake or textile dyes. In all cases, no higher mutagenicity in slow NAT2 acetylators could be established when compared to these or rapid acetylators, and in fact among individuals exposed to urban pollution, rapid acetylators showed a higher mutagenicity in urine than slow acetylators. In a study investigating the influence of NAT genotypes in the association between permanent hair dyes and bladder cancer, a significant association of the slow NAT2 acetylation genotype was identified. However these findings could not be replicated in other studies.
  
  
Entity Breast cancer
Prognosis After dozens of studies involving several thousands of breast cancer patients, as well as meta-analyses, today it is obvious that no major association of NAT2 polymorphism and breast cancer risk exists.
  
  
Entity Head and neck cancer
Prognosis Since chemical compounds present in tobacco are inactivated by phase II enzymes, it has been proposed that head and neck cancer risk could be modified by NAT genotypes. However, overall findings indicate that no relevant association between NAT2 polymorphism and head and neck cancer risk is to be expected.
  
  
Entity Other diseases
Disease Although a relation of risk may be definitely discarded for systemic lupus erythematosus (SLE), inflammatory bowel disease and endometriosis, more research is needed for rheumatoid arthritis, Parkinson's, Alzheimer's, Behçet's and periodontal diseases, as current results are inconclusive but suggest a possible relation with NAT2 polymorphism. In diabetes mellitus the possible relation with the rapid phenotype may be due to acquired metabolic changes and more genotyping studies are needed. NAT2 slow metabolizers are more prone to the side effects of polymorphically acetylated drugs, as is the SLE-like syndrome induced by hydralazine and procainamide, the side effects due to sulphasalazine and the skin rash secondary to many sulphonamides.
  

To be noted

Large interethnic and intraethnic variability exists in the frequency for common SNPs at the NAT2 gene. Future association studies should take into consideration such differences and ambiguous NAT2 genotypes.

Bibliography

Unraveling ambiguous NAT2 genotyping data.
Agundez JA, Golka K, Martinez C, Selinski S, Blaszkewicz M, Garcia-Martin E.
Clin Chem. 2008 Aug;54(8):1390-4.
PMID 18664443
 
N-acetyltransferases: lessons learned from eighty years of research.
Agundez JA.
Curr Drug Metab. 2008 Jul;9(6):463-4.
PMID 18680465
 
N-acetyltransferases as markers for asthma and allergic/atopic disorders.
Batra J, Ghosh B.
Curr Drug Metab. 2008 Jul;9(6):546-53.
PMID 18680475
 
Molecular mechanism of slow acetylation of drugs and carcinogens in humans.
Blum M, Demierre A, Grant DM, Heim M, Meyer UA.
Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5237-41.
PMID 1675794
 
Human arylamine N-acetyltransferase genes: isolation, chromosomal localization, and functional expression.
Blum M, Grant DM, McBride W, Heim M, Meyer UA.
DNA Cell Biol. 1990 Apr;9(3):193-203.
PMID 2340091
 
Regulation of arylamine N-acetyltransferases.
Butcher NJ, Tiang J, Minchin RF.
Curr Drug Metab. 2008 Jul;9(6):498-504.
PMID 18680469
 
Genetically determined variability in acetylation and oxidation. Therapeutic implications.
Clark DW.
Drugs. 1985 Apr;29(4):342-75.
PMID 2859977
 
Possible implications of doxycycline-rifampin interaction for treatment of brucellosis.
Colmenero JD, Fernandez-Gallardo LC, Agundez JA, Sedeno J, Benitez J, Valverde E.
Antimicrob Agents Chemother. 1994 Dec;38(12):2798-802.
PMID 7695265
 
Agranulocytosis during combined procainamide and phenytoin therapy.
Crook JE, Woosley RL, Leftwich RB, Natelson EA.
South Med J. 1979 Dec;72(12):1599-601.
PMID 515773
 
Genetic control of isoniazid metabolism in man.
Evans DA, Manley KA, McKusick VA.
Br Med J. 1960 Aug 13;2(5197):485-91.
PMID 13820968
 
The determination of the isoniazid inactivator phenotype.
Evans DA, Storey PB, Wittstadt FB, Manley KA.
Am Rev Respir Dis. 1960 Dec;82:853-61.
PMID 13697556
 
Interethnic and intraethnic variability of NAT2 single nucleotide polymorphisms.
Garcia-Martin E.
Curr Drug Metab. 2008 Jul;9(6):487-97.
PMID 18680468
 
Nucleotide sequence of an intronless gene for a human arylamine N-acetyltransferase related to polymorphic drug acetylation.
Grant DM, Blum M, Demierre A, Meyer UA.
Nucleic Acids Res. 1989 May 25;17(10):3978.
PMID 2734109
 
Evidence for two closely related isozymes of arylamine N-acetyltransferase in human liver.
Grant DM, Lottspeich F, Meyer UA.
FEBS Lett. 1989 Feb 13;244(1):203-7.
PMID 2924904
 
Structures of human arylamine N-acetyltransferases.
Grant DM.
Curr Drug Metab. 2008 Jul;9(6):465-70.
PMID 18680466
 
Molecular genetics of human polymorphic N-acetyltransferase: enzymatic analysis of 15 recombinant wild-type, mutant, and chimeric NAT2 allozymes.
Hein DW, Ferguson RJ, Doll MA, Rustan TD, Gray K.
Hum Mol Genet. 1994 May;3(5):729-34.
PMID 8081359
 
Influence of polymorphic N-acetyltransferases on non-malignant spontaneous disorders and on response to drugs.
Ladero JM.
Curr Drug Metab. 2008 Jul;9(6):532-7.
PMID 18680473
 
Human N-acetyltransferases and drug-induced hepatotoxicity.
Makarova SI.
Curr Drug Metab. 2008 Jul;9(6):538-45.
PMID 18680474
 
Effect of environmental substances on the activity of arylamine N-acetyltransferases.
Rodrigues-Lima F, Dairou J, Dupret JM.
Curr Drug Metab. 2008 Jul;9(6):505-9.
PMID 18680470
 
Arylamine N-acetyltransferases in mycobacteria.
Sim E, Sandy J, Evangelopoulos D, Fullam E, Bhakta S, Westwood I, Krylova A, Lack N, Noble M.
Curr Drug Metab. 2008 Jul;9(6):510-9.
PMID 18680471
 
Structure of arylamine N-acetyltransferase reveals a catalytic triad.
Sinclair JC, Sandy J, Delgoda R, Sim E, Noble ME.
Nat Struct Biol. 2000 Jul;7(7):560-4.
PMID 10876241
 
Structure/function evaluations of single nucleotide polymorphisms in human N-acetyltransferase 2.
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Curr Drug Metab. 2008 Jul;9(6):471-86.
PMID 18680467
 
The mechanism of isoniazid acetylation by human N-acetyltransferase.
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PMID 5678219
 
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Citation

This paper should be referenced as such :
Ruiz, JD ; Agúndez, JAG ; Martinez, C ; Garcia-Martin, E
NAT2 (N-acetyltransferase 2 (arylamine N-acetyltransferase))
Atlas Genet Cytogenet Oncol Haematol. 2009;13(12):952-955.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/NAT2ID41498ch8p22.html


External links

Nomenclature
HGNC (Hugo)NAT2   7646
Cards
AtlasNAT2ID41498ch8p22
Entrez_Gene (NCBI)NAT2  10  N-acetyltransferase 2
AliasesAAC2; NAT-2; PNAT
GeneCards (Weizmann)NAT2
Ensembl hg19 (Hinxton)ENSG00000156006 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000156006 [Gene_View]  chr8:18391245-18401213 [Contig_View]  NAT2 [Vega]
ICGC DataPortalENSG00000156006
TCGA cBioPortalNAT2
AceView (NCBI)NAT2
Genatlas (Paris)NAT2
WikiGenes10
SOURCE (Princeton)NAT2
Genetics Home Reference (NIH)NAT2
Genomic and cartography
GoldenPath hg38 (UCSC)NAT2  -     chr8:18391245-18401213 +  8p22   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)NAT2  -     8p22   [Description]    (hg19-Feb_2009)
EnsemblNAT2 - 8p22 [CytoView hg19]  NAT2 - 8p22 [CytoView hg38]
Mapping of homologs : NCBINAT2 [Mapview hg19]  NAT2 [Mapview hg38]
OMIM243400   612182   
Gene and transcription
Genbank (Entrez)AI460128 AJ581144 AJ581145 AJ581146 AJ581147
RefSeq transcript (Entrez)NM_000015
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)NAT2
Cluster EST : UnigeneHs.2 [ NCBI ]
CGAP (NCI)Hs.2
Alternative Splicing GalleryENSG00000156006
Gene ExpressionNAT2 [ NCBI-GEO ]   NAT2 [ EBI - ARRAY_EXPRESS ]   NAT2 [ SEEK ]   NAT2 [ MEM ]
Gene Expression Viewer (FireBrowse)NAT2 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)10
GTEX Portal (Tissue expression)NAT2
Protein : pattern, domain, 3D structure
UniProt/SwissProtP11245   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP11245  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP11245
Splice isoforms : SwissVarP11245
Catalytic activity : Enzyme2.3.1.5 [ Enzyme-Expasy ]   2.3.1.52.3.1.5 [ IntEnz-EBI ]   2.3.1.5 [ BRENDA ]   2.3.1.5 [ KEGG ]   
PhosPhoSitePlusP11245
Domains : Interpro (EBI)Arylamine_N-AcTrfase   
Domain families : Pfam (Sanger)Acetyltransf_2 (PF00797)   
Domain families : Pfam (NCBI)pfam00797   
Conserved Domain (NCBI)NAT2
DMDM Disease mutations10
Blocks (Seattle)NAT2
PDB (SRS)2PFR   
PDB (PDBSum)2PFR   
PDB (IMB)2PFR   
PDB (RSDB)2PFR   
Structural Biology KnowledgeBase2PFR   
SCOP (Structural Classification of Proteins)2PFR   
CATH (Classification of proteins structures)2PFR   
SuperfamilyP11245
Human Protein AtlasENSG00000156006
Peptide AtlasP11245
HPRD02000
IPIIPI00004421   IPI00789198   
Protein Interaction databases
DIP (DOE-UCLA)P11245
IntAct (EBI)P11245
FunCoupENSG00000156006
BioGRIDNAT2
STRING (EMBL)NAT2
ZODIACNAT2
Ontologies - Pathways
QuickGOP11245
Ontology : AmiGOarylamine N-acetyltransferase activity  protein binding  cytosol  plasma membrane  xenobiotic metabolic process  L-amino acid transmembrane transporter activity  L-alpha-amino acid transmembrane transport  
Ontology : EGO-EBIarylamine N-acetyltransferase activity  protein binding  cytosol  plasma membrane  xenobiotic metabolic process  L-amino acid transmembrane transporter activity  L-alpha-amino acid transmembrane transport  
Pathways : KEGGCaffeine metabolism    Drug metabolism - other enzymes    Chemical carcinogenesis   
REACTOMEP11245 [protein]
REACTOME PathwaysR-HSA-156582 [pathway]   
NDEx NetworkNAT2
Atlas of Cancer Signalling NetworkNAT2
Wikipedia pathwaysNAT2
Orthology - Evolution
OrthoDB10
GeneTree (enSembl)ENSG00000156006
Phylogenetic Trees/Animal Genes : TreeFamNAT2
HOVERGENP11245
HOGENOMP11245
Homologs : HomoloGeneNAT2
Homology/Alignments : Family Browser (UCSC)NAT2
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerNAT2 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)NAT2
dbVarNAT2
ClinVarNAT2
1000_GenomesNAT2 
Exome Variant ServerNAT2
ExAC (Exome Aggregation Consortium)NAT2 (select the gene name)
Genetic variants : HAPMAP10
Genomic Variants (DGV)NAT2 [DGVbeta]
DECIPHERNAT2 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisNAT2 
Mutations
ICGC Data PortalNAT2 
TCGA Data PortalNAT2 
Broad Tumor PortalNAT2
OASIS PortalNAT2 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICNAT2  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDNAT2
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)Pharmacogenomics of Infectious Diseases (PGx_IfD )
BioMutasearch NAT2
DgiDB (Drug Gene Interaction Database)NAT2
DoCM (Curated mutations)NAT2 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)NAT2 (select a term)
intoGenNAT2
NCG5 (London)NAT2
Cancer3DNAT2(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM243400    612182   
Orphanet19370   
MedgenNAT2
Genetic Testing Registry NAT2
NextProtP11245 [Medical]
TSGene10
GENETestsNAT2
Target ValidationNAT2
Huge Navigator NAT2 [HugePedia]
snp3D : Map Gene to Disease10
BioCentury BCIQNAT2
ClinGenNAT2
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD10
Chemical/Pharm GKB GenePA18
Clinical trialNAT2
Miscellaneous
canSAR (ICR)NAT2 (select the gene name)
Probes
Litterature
PubMed499 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineNAT2
EVEXNAT2
GoPubMedNAT2
iHOPNAT2
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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